The purpose of these experiments is to give a better understanding of the mode of action of selected antitumor agents by conducting in vitro and in vivo studies with mouse tumor systems. L1210 leukemia was used to measure drug effects. Investigations are being conducted with 5-aza-2'-deoxycytidine (DAC), dihydro-5-azacytidine (DHAC) and the arabinoside analogue of 5-azacytidine (ARA-AC). The refractory nature of a few L1210 cells to treatment with the most potent of these three compounds, DAC, become apparent during these investigations. Even though DAC can kill 7 logs of L1210 in vivo it is limited to 3-4 log cell kill in vitro (clonogenic assay). DAC can cure mice with L1210 if treatment is early after tumor transplant (day 1) but can cure no mice when treatment is delayed. Neither millimolar thymidine nor 3-deaza-uridine in combination with DAC increase therapeutic effects, which indicates deoxycytidine kinase poor mutants are not responsible for the refractoriness. Combination of DAC and cytoxan or BCNU do lead to cures with late treatment of L1210. These findings suggest that the refractory nature of L1210 to DAC therapy may be due to pharmacological sanctuaries and to dormancy or latency of L1210 resulting from DAC treatment. We have preliminary in vitro evidence to suggest this latter possibility and are pursuing further evidence.